Post-translational modification of proteins by ubiquitin and ubiquitin family members such as SUMO (Small Ubiquitin-like Modifier) are highly conserved processes in eukaryotes that are essential for cell viability. The roles of ubiquitin in signaling and in targeting proteins for proteosome-mediated degradation have been well-documented. SUMO is not as thoroughly understood as ubiquitin, largely due to the lack of small molecule inhibitors of the pathway. The goal of this proposal is to identify small molecules that inhibit the SUMOylation pathway. This will be accomplished in two stages: (1) by performing a large-scale chemical genetic screen for compounds that inhibit the SUMO pathway in vivo, and (2) by performing secondary assays on the hits from the primary chemical genetic screen to identify those molecules that directly inhibit SUMOylation. Inhibitors identified through this project will serve as reagents for studying the varied roles of SUMO in vivo, with strong potential for broader application in elucidating the roles of SUMO in human health and disease. PUBLIC HEALTH RELEVANCE: Proteins are modified in many ways that affects their activity in the cell. A critically important yet poorly understood protein modification is called SUMOylation. Proteins that are involved in cancer, neural degeneration, microbial infection, and the immune response are all SUMOylated. A major stumbling block for further understanding the roles of SUMOylation is the lack of an effective drug that targets the pathway. The goal of this project is to take the first steps for developing a SUMO-specific drug.